Letter pubs.acs.org/OrgLett
Copper-Mediated Construction of Spirocyclic Bis-oxindoles via a Double C−H, Ar−H Coupling Process Pauline Drouhin, Timothy E. Hurst, Adrian C. Whitwood, and Richard J. K. Taylor* Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K. S Supporting Information *
ABSTRACT: A double C−H, Ar−H coupling process for the conversion of bis-anilides into spirocyclic bis-oxindoles, enabling the concomitant formation of two all-carbon quaternary centers at oxindole 3-positions in a diastereoselective manner, is described. The optimum cyclization conditions utilize stoichiometric Cu(OAc)2·H2O/KOtBu in DMF at 110 °C and have been applied to prepare a range of structurally diverse bis-spirooxindoles in fair to good yields (28−77%); the method has also been extended to prepare bis-oxindoles linked by a functionalized acyclic carbon chain.
O
ing multiple spiro-quaternary carbon centers. The majority of approaches rely on the linking together of preformed oxindoles,2−4 a strategy most beautifully illustrated by Barbas who developed an organocatalytic asymmetric Michael addition/aldol cascade reaction between 3-substituted oxindoles and methyleneindolinones which proceeds with excellent diastereo- and enantiocontrol (Scheme 1, eq 1).6 Related variants have subsequently been reported7 but all commence with preformed oxindoles and all produce bis-oxindole
ver the past decade, there has been a significant resurgence of interest in oxindoles, as these structures represent validated targets in the search for new drug candidates and form the cornerstone of numerous alkaloids of biological interest.1 More recently, bis-oxindoles have attracted considerable attention (Figure 1). For example,
Scheme 1. Strategies for the Synthesis of Bis-oxindoles
Figure 1. Examples of bis-oxindole targets.
Natura (1) is representative of a family of isoindigo-based anticancer agents (CDK inhibitors)2 and compound 2 is typical of a range of dispirooxindole-pyrrolidine derivatives recently shown to possess significant antibacterial and anticancer activities (against A549 human lung adenocarcinoma).3 Moreover, bis-oxindoles have long been employed as precursors of bis(pyrroloindoline) alkaloids,4 most recently with compound 3 being used as a cornerstone for the synthesis of a diverse range of cyclotryptamine alkaloids.4d Many synthetic strategies have been established to access the oxindole motif,5 but only limited examples have been reported to date on bis-oxindoles, probably because of their highly functionalized polycyclic skeletons, particularly those contain© 2014 American Chemical Society
Received: August 14, 2014 Published: September 8, 2014 4900
dx.doi.org/10.1021/ol5024129 | Org. Lett. 2014, 16, 4900−4903
Organic Letters
Letter
products linked at the 3,3-positions by another 5-membered ring generated in a formal [3 + 2]-cyclization process.8 Our objective was to establish a more general route to bisoxindoles (Scheme 1, eq 2) which would utilize readily accessible bis-anilide precursors9 and would be applicable to the formation of a range of diverse bis-oxindole products with, for the first time, great variability in the linking central core units. As shown, the plan was to utilize a copper(II)-mediated bisanilide cyclization approach (a formal C−H, Ar−H coupling) based on the chemistry devised for the preparation of oxindoles10,11 and related heterocycles12 by the groups of Taylor and Kündig in 2009. Herein, we wish to disclose the success of this approach to access a range of bis-spirooxindoles featuring central core units of different ring sizes and, in addition, functionalized acyclic linker units. The cyclopentanone 2,5-dicarboxamide 4a was chosen as the bis-anilide for preliminary studies (Table 1). Compound 4a was
Figure 2. Crystal structure of 5a (50% probability ellipsoids).
substrate scope using a range of substituted bis-anilides 4.15 First we ensured that the procedure was compatible with Nbenzyl protection and found that adduct 5b was formed in 57% yield. Substitution of the aromatic rings was studied next, and both 4-methyl- and 4-methoxy-substitution was well tolerated giving 5c and 5d, respectively. Unsymmetrical bis-oxindoles were also prepared with either differential ring substitution (5e) or differential N-protection (5f). Variation of the central ring size was also explored.15 Thus, a cyclohexanone (5g) and a substituted cyclohexanone example (5h) were prepared, as were a 7-membered ring-containing bis-oxindole (5i, obtained in 77% yield) and a benzo-fused cycloheptanone example (5j). The yields of the cyclization products varied (28−77%), but it should be noted that all of the procedures in Scheme 2 used the standard conditions developed in Table 1 and none were optimized. It should also be noted that all of products in Scheme 2 were obtained as single trans-diastereoisomers.
Table 1. Optimization of the Reaction Conditions
entry
base
1
−
2
−
3
−
4
KOtBu (2.2 equiv)
Cu source Cu(OAc)2·H2O (1.0 equiv) Cu(OAc)2·H2O (1.0 equiv) Cu(OAc)2·H2O (1.0 equiv) Cu(OAc)2·H2Oa (2.0 equiv)
solvent (temp) mesitylene (170 °C) toluene (100 °C) toluene (80 °C) DMF (110 °C)
time (h)
yield
0.5
